Surfactant protein C (SP-C) is a lung specific, hydrophobic protein. Over 35 single allelic mutations have been identified in the surfactant protein C gene (SFTPC) that cause respiratory disease of varying severity and age of onset from the newborn period to adulthood. The lung disease associated with mutations in SFTPC is thought to result from aggregation of misfolded or misrputed proSP-C peptides that fail to be processed into the mature form, overwhelm the capacity of cellular quality control pathways, and activate the unfolded protein response (UPR). The UPR consists of multiple intracellular signaling pathways that decrease protein synthesis by decreasing general RNA translation, increase degradation of accumulated proteins, and increase the protein folding and secretion capacity of the endoplasmic reticulum (ER). Theoretically, dysregulation of any component of the UPR may alter its capacity to maintain cellular homeostasis and may unmask expression of variants in SFTPC. Thus, the hypothesis of this proposal is that variants in SFTPC and components of the unfolded protein response interact to increase the risk and severity of lung disease in newborns. The first aim is to use complete resequencing to determine the phenotype-based frequency of variants of the SFTPC gene for 500 race-matched patients with and without RDS and to identify whether previously unrecognized or other potentially significant variants are present in infants with RDS. The second aim is to determine a phenotype-based frequency of variants in seven of the key genes that encode regulatory factors of the unfolded protein response for these same 500 patients using an Illumina panel of tagSNPs. Finally, the third aim is to look at the interaction of SFTPC variants with genes of the UPR that increase the risk for RDS using sequential logistic regression. [unreadable] [unreadable] [unreadable] [unreadable]